Preparation of acetoacetyl aromatic acid amides



Patented Apr. 4, 1939 UNITED STATES PATENT OFFICE PREPARATION or ACETOACETYL ARO- MATIC scm AMIDES No Drawing.

Application September 28, 1937,

Serial No. 166,127

10 Claims.

This invention relates to the production of acetoacetyl aromatic acid amides by reacting diketene with an aromatic primary mono or poly-amine or substituted aromatic primary amine, in the presence of an inert volatile solvent for the reactants, and preferably a medium or a low-boiling inert solvent in which the acetoacetyl aromatic amide is quite soluble when hot, such as acetone, dioxan, benzene and toluene.

The production of acetoacetanilide by reacting aniline and diketene already is known; and the process therefor is covered in U. S. Patent 1,982,675 issued December 4, 1934, to George H. Law.

It has now been discovered that by reacting diketene with the higher primary aromatic monoamines, primary aromatic poly-amines, and with substituted primary aromatic monoand polyamines, under conditions where the speed and violence of the reaction and the temperature of the reaction mixture is at all times under control, it is readily possible to produce acetoacetic acid amides from such amines and substituted amines in very satisfactory yields.

According to the invention, diketene'and such a primary aromatic amine or substituted amine are slowly reacted in the presence of a. solvent for the reactants which is inert with respect to each, and in which the resultant amide is soluble. Preferably the diketene is introduced slowly into an agitated solution of the amine'in the inert solvent, at an elevated temperature which is desirably around the boiling point or refluxing point thereof. After completion of the reaction, the solvent is removed by distillation, and the acetoacetic acid amide is separated from any unreacted amine and recovered. Thus. notwithstanding the powerful polymerization tendency of diketene, and the high chemical reactivity of primary-monoand poly-amines and substituted amines, including those derived from aromatic hydrocarbons containing in their molecules two or more interconnected benzene nuclei, either condensed or uncondensed, it is possible,- by utilizing the present invention,to prepare from these compounds valuable acetoacetyl aromatic amides with good yields and efiiciencies.

Bis-para-amine derivatives of diphenyl and its homologues, amino diphenylm'ethane, a and finaphthylamines and their homologues, and aralkyl amines such as benzylamine and its homologues, exemplify aromatic amines which react with diketene to yield these acetoacetyl amides.

The following examples serve to illustrate the invention:

Exlmrna 1 Preparation of bis-acetoacetyl orthotolidine A solution of 212 grams (1 mol) of orthotolidine in 2100 cc. of acetone was heated under reflux to the boiling point of acetone, and 176 grams (1.05 mol) of diketene was slowly added over a period of 15 minutes while constantly stirring the mixture. After approximately an hour the reaction product began to separate. Refiuxing was continued for 3 hours and the reaction mixture, a free-flowing crystalline slush, was then allowed to stand overnight, and the crystallized product was separated .by filtration. There thus was obtained 245 grams of bis-acetoacetyl orthotolidine which melted at 203 to 204 C. The filtrate was concentrated to half its original volume by distillation, cooled, and a further 29 grams of the bis-acetoacetyl orthotolidine,

melting point 202 to 203 C., was obtained. On further concentration, an additional 63 grams of bis-acetoacetyl orthotolidine, melting point 201 to 202 C., was obtained which was separated by filtration and washed with acetone.

Thus a yield of diacetoacetyl tolidine of 88.7% was secured, based upon the orthotolidine, with a diketene efliciency of 84.9% based upon diacetoacetyl tolidine. Acetone, was removed by distillation from the mother liquor from the final filtration and the residue treated with 200 cc. of a 5% aqueous sodium hydroxide solution. The caustic alkali-insoluble material, consisting chiefly of diacetyl orthotolidine, was separated by filtration. TheJiltrate was then acidified with 25 cc. of concentrated hydrochloric acid, and the precipitated diacetoacetyl orthotolidine separated on a filter, washed, and air dried. There was obtained an additional 8 grams of somewhat impure diacetoacetyl orthotolidine which melted at 195' to 200 C., increasing the total yield to 90.8%. As acidifying agents, other acids, such as sulfuric or acetic, may be used.

The reaction involved is indicated by the equa tion:

(o-Tolidine) (Diketene) omooomoonnQ-Q-nnooomooom I HI Exams 2 Preparation of bis-acetoacetfll bensidine To a solution of 36.8 grams or benzidine (bis melted with decomposition at 233 C. The seetone extract was evaporated, and yielded 10.6 grams of a caustic alkali-insoluble material. The residue was suspended in 100 cc. of warm acetone,

and the resulting suspension filtered while warm.

There was obtained 4.6 grams of acetone-insoluble diacetyl benzidine, melting at from 325' to 330 0. Concentration of the acetone filtrate yielded 4.2 grams of monoacetyl benzidine, melting at from 193' to 195 C. The percentage conversion of the benzldine was and the yield of the bis-acetoacetyl benzidine on the basis of the amount of benzidine that reacted was 97.5%.

. Exams: 3 Production of acetoacet-alpha-naphthvlamide To a cold solution of 8.4 grams of diketene in 50 cc. of dioxan was added in the cold a solution of 14.3 grams of alpha--naphthylaminein 50 cc. of dioxan. After 24 hours the odor of diketene had disappeared, and a portion of the reaction product had crystallized from the solution. Addition of petroleum ether caused a further precipitation. The crystallized reaction product was separated by filtration of the mixture, washed with petroleum ether, and then was recrystallized from benzene. A yield of over was obtained of the acetoacet-alpha-naphthylamlde in the form of almost colorless needles which melted at 118 to C.

\ By introducing diketene to a refluxing solution of the alpha-naphthylamine in dioxan, the reaction may be completed in a shorter time.

The equation for the reaction may be written as follows: I

I Under conditions substantially idenucar with those recited in'Example 3, supra, but using betanaphthylamine instead of alpha-naphthylamine, a yield of over 90% of acetoacet-beta-naphthylamide, melting at 100 to 102 0., was produced and recovered.

The acetoacetyl aromatic acid amides of theinvention are in general used in the dyestuif industry as intermediates for the production of dyes of the Hausa yellow type. They also, under ring closure in the presence of dehydrating agents,

form hydroxymethyl quinoline derivatives. Di-- acetoacetyl tolidine, known as NaphthoiAs-Qis a commercially important dyestufi' component.

The following examples illustrate the production of substituted'aacetoacetanilides in accordance with the invention:

m 0 Para-hydro acetoac etanilide To a refluxing solution of 10.9 grams of paraamino-phenol in cc. of acetone 8.4 grams of diketene was added dropwise. After refluxins the mixturefor one hour, the acetone was re-.

no-Owmoooaioocri.

Pan-hydroxy aostoaoetsnilide formed by the reaction of one molof diketene with one or the amine.

I Exulru: 6 v Para-nitroacetoccetaniltde To a refluxing solution of 50 grams of paranitroaniline in 600 cc. of acetone 33.4 grams of diketene were added dropwise. After refluxing the solution for 4 hours, the acetone was distilled oil, and the resultant crystalline residue was treated with a dilute solution of the theoretical amount of sodium hydroxide for dissolving the resultant amide. The unreacted para-nitroaniline then was separated by filtration. The filtrate was neutralized with the dilute hydrochloric acid, whereupon para-nitroacetoacetanilide precipitated. This was filtered off, washed with water, and air-dried, giving a yield of 65% thereof. When recrystallized from water it occurred as a pale yellow crystalline compound which melted at 124 to 124.5 C. It has the apparent structure indicated by the formula NHOOOHrOOOHs Psra-nitroaeetoaoetanilide and is formed by the reaction of equimolecular proportions of the reactants.

Para-ethoru acet'oacetanilide To a refluxing solution of 34 grams of paraphenetidine in 250 cc. of acetone was added slowly 21 grams of diketene. The heat developed by the resultant reaction was sufllcient to keep the solution gently refluxing without external appllcation of heat. when addition of the diketene was completed, the acetone was removed by dis-1 tillation. The residue solidified upon cooling; and it was purified by recrystallization from a mixture of ethyl acetate and petroleum ether. Thus were obtained 48 grams of para-ethoxy aceto-acetanillde, occurring as colorless needles melting at between 101 and 102 0., and corresponding to a yield of around 874%. This product has the apparent structure mmwO-miooomcocm Para-etboxy aestoaoatanllldo and results from the interaction of equimolecular proportions of the reactants.

Exams 8 Ortho-methoa:u aoetoacetanilide Following the procedure described in Example 7 and using 31 grams of ortho-anisidine and 21 grams of diketene there were obtained 45 grams of ortho-methoxy acetoacetanilide in the term of colorless platelets, which melt at between 85 and 86 0., corresponding to a yield oi around 87%. The compound has the apparent structure NHCOCHSCOOHI O CH:

Ortho-methoxy aeetoscetanillde EXAMPLE-'9 Diacetoacetyl meta-phenylene diamine To a refluxing solution of 27 grams oi metaphenylene diamine in 250 cc. of acetone, 47 grams of diketene were added dropwise. Thereafter the acetone solution was concentrated and cooled, whereupon an almost quantitative yield of diacetoacetyl meta-phenylene diamine crystallized out and was filtered off and air-dried. Upon recrystallization form glacial acetic acid, it occurred as a colorless crystalline compound that melted at between 107 and 108 C. and was soluble in water, alcohols, ketones, esters, and ethers, but was practically insoluble in chlorinated s01- vents and in aromatic and aliphatic hydrocarbons. It has the apparent structure NHCOCHiCOCHi NHC OCHaCOCH:

Diacetoacetyl meta-plienylene dlamine ExAuPLn 10 Diacetoacetyl para-phenulene diamine Upon adding 46.2 grams of diketene slowly to a refluxing solution of 27 grams of para-phenylene diamine in 375 cc. of acetone, an initial yield of 52 grams of diacetoacetyl para-phenylene diamine separated rapidly from solution, which was separated by filtration from the reaction mixture after cooling the latter. The filtrate upon further concentration yielded an ad ditional 12 grams of this product, thereby providing a total yield of 92.5%; after purification by recrystallization with water it occurs as a lustrous pearl gray crystalline compound which melts at between 176 and 178 C. and has the apparent structure:

NHCOCHtCOCHI NH 0 0 CHQC 0 OH: Diacetoacetyl para-phenylene diemine hydrocarbons.

NHCOCHrGO OH:

A refluxing solution of 60.5 grams of 2-amino-1,3-dimethyl benzene in 400 cc. of benzene was reacted with 42 grams of diketene by adding the latter dropwise to the solution over a period of 30 minutes. The resultant. solution was then concentrated to 200 cc. and, after cooling to room temperature, the product which crystallized out was filtered, washed with a little ether, and airdried. There was obtained 83 grams of 2,6-dimethyl acetoacetanilide, (representing a total yield of around 81%), in the form of a colorless crystalline material which melts at 135 to 137 C. This compound is soluble in ethanol and other alcohols, acetone and other ketones, and benzene and other aromatic hydrocarbons, but is only slightly soluble inethers and aliphatic It is insoluble in water, but completely soluble in dilute aqueous caustic alkali solutions.

EXAMPLE 12 Preparation of Z-methyl acetoacetam'lide NHCOCHiCOCH:

To a solution of 281 grams of ortho-toluidine in 1200 cc. of toluene at 45 C. was added dropwise, during a period of one hour, 220 grams of diketene. the temperature during the reaction being kept below 75 C. Afte'rcooling to C., the product which separated was filtered and air-dried, yielding 397 grams of 2-methyl acetoacetanilide. From the filtrate, after concentration to 600 00., an additional 33 grams of prodnot was obtained, making a total yield of 430 grams, (or a yield of around 85.8% based upon the orthotoluidine employed). 2-methyl acetoacetanilide is a colorless crystalline material which melts at 104 to 106 C. It is soluble in alcohols, esters, ketones, and aromatic hydrocarbons, practically insoluble in ethers, aliphatic hydrocarbons, and water, but completely soluble in dilute caustic alkali solutions.

Exmrm 13 Preparation of 2,5-dichl01' acetoacetanilide 01 NHCOCHQCOCH! To a refluxing solution of 60 grams of 2,5-dichlor aniline in 200 cc. of benzene, 33 grams of diketene were added slowly over a period of one hour. Refluxing was continued for another hour. Then 75 cc. of benzene were distilled off, and the reaction mixture cooled to 20 C. The product ch separated was filtered, washed with petroleum ether and dried, yielding 80 grams of 2,5- dichlor acetoacetanilide, corresponding to a yield of 87.8% thereof. This compound is a colorless crystalline solid which melts at 94 to 96 C. Itis soluble in aromatic hydrocarbons; is insoluble in ethers, aliphatic hydrocarbons and water; and is completely soluble in dilute aqueous caustic alkali solutions.

Preparation of 3,5-dimethgl-acetoacetanilide OH OOOHaOOCHI To a refluxing solution of 60.5 grams of metaxylidine in 300 cc. ofbenzene 42 grams of diketene were added dropwise over a period of 30 minutes. Afterwards, the solution was concentrated to 150 cc. and cooled to room temperature. The product which crystallized out was separated on a filter, washed with a little diethyl ether, and air-dried. Thus were obtained 69' grams of 3,5-dimethyl acetoacetanilide as a colorless crystalline solid which melted at 90 to 92 C. Twelve additional grams of this compound were secured by further concentrating the filtrate. A total yield thereof equivalent to 70.2% of the meta-xylidine reacted was secured. 3,5-dimethyl acetoacetanilide is soluble in alcohols, ketones, and aromatic hydrocarbons, but

lized for the production of acetoacetyl acid amides from aniline homoiogues and other aromatic primary monoand poly-amines derived from simple and condensed aromatic hydrocarbons, and from other substituted aromatic monoand polyamines, such as those in which there is directly attached to at least one carbon atom of the henzene ring a radical selected from the group consisting of hydroxyl, nitro, amino, chloro,'bromo,-

and alkoxy radicals.

Among inert volatile solvents for the aromatic primary amines suitable for use in the present invention may be mentioned,-in addition to aromatic hydrocarbons, such as benzene and tolu-' ene,dioxan, acetone and other aliphatic ketones, and other lowor medium-boiling'inert solvents. The use of acetone is much preferred from a production standpoint.

By the expression "higher aromatic mono-amines" occurring in the specification andclaims, it is intended to designate those primary amines having more than 6 carbon atoms in their mole- 0 es.

The term primary amines having at least two directly interconnected benzene nuclei in the molecule" is intended to include those amines wherein the interconnected benzene nuclei are either condensed, as in the case of the naphthyl- I amines, or are uncondensed.

F the carbon atoms of the benzene ring.

The present application is a continuation-in-- part of applicant's copending application Serial No.'89,'l'l8 filed July 9, 1936 entitled Prepara- I tion of acetoacetyl aromatic acid amides".

The invention is susceptible of modification within the scope of the appended claims.

I claim: p

1. Process for preparing an acetoacetyl aro- I arcane? mama 14 matic acid amide, which comprises heating and reacting diketene with a primary aromatic amine selected from the group consisting of .amines having at least two directly interconnected benzene nuclei in the molecule, and those substituted aromatic amines in which there is directly. attached to a carbon atom of the ring at least one halogen radical, in the presence of a solvent inert to the reactants, and recovering from the resultant reaction mixture the acetoacetyl aromatic acid amide thus produced.

2. Process for preparing an acetoacetyl aromatic acid. amide, which comprises heating and reacting diketene with an aniline homologue in the presence of a solvent inert to the reactants. and recovering from the resultant reactionmixture the acetoacetyl aromatic acid amide thus produced.

8. Process as defined in claim 2 wherein the said aniline homologue has at least one methylgroup directly connected with a carbon atom of thebenzene ring.

4. Process for preparing an acetoacetyl aromatic acid amide, which comprises heating and reacting diketene with a chlor aniline, in the presence of a solvent inert to the reactants, and

separately recovering the acetoacetyl aniline thus produced.

5. Method of preparing an acetoacetyl amide of a naphthalene, which comprises reacting diketene and a naphthylamine in the presence of an inert solvent for the reactants, and thereafter recovering the acetoacet-naphthylamide from the resultant reaction mixture.

6. As a chemical compound, 2,5-dichlor acetoacetanilide, the same being a crystalline com-, pound melting at 94 to 96 C., and being soluble in aromatic hydrocarbons, and dilute caustic alkali solutions, and insoluble in ethers, water, and aliphatic hydrocarbons.

'1. Process for preparing an acetoacetyl aromatic amide, which comprises slowly introducing diketene in small successive portions into an agitated solution in an inert volatile solvent of a primary aromatic amine having at least two directly interconnected benzene nuclei in the molecule, and recovering from the resultant reaction mixture the acetoacetyl amide thus produced.

'8. Process for preparing an acetoacetyl aromatic amide, which comprises slowly introducing diketene in small successive portions into an agitated solution in a volatile solvent of a primary aromatic amine having two condensed benzene nuclei in the molecule, thesaid solvent being inert toward the reactants, and recovering from' the resultant reaction mixture the acetoacetyl primary aromatic amine selected from the group consisting of amines having at least two directly interconnected benzene nuclei in the molecule, and those substituted aromatic amines in which at least one halogen radical is directly attached to a carbon atom of the ring, and recovering from the. resultant reaction mixture the acetoacetyl aromatic amide thus produced.

10. Process as defined in claim 9, wherein the diketene is slowly introduced in small successive portions into a refluxing solution of the said primary aromatic amine in an inert volatile solvent.

ALBERT B. BOESE, JR. 

